Prostaglandins are a sub-class of eicosanoids found in most body tissues and implicated in a variety of physiological functions in animals, including smooth muscle contraction, reproduction, autoimmunity, inflammation, reduction of intraocular pressure, etc. Prostaglandin E2 (PGE2) has been associated with various physiological and/or pathological conditions such as stimulation of bone formation, increase in bone mass, arthritis, pain, inflammation, cancer, multiple sclerosis, etc.
PGE2 binds to four receptors (EP1, EP2, EP3 and EP4). The EP4 receptor is associated with intracellular cyclic adenosine monophosphate (cAMP) production, and is distributed in a wide variety of tissue types, suggesting a major role in PGE2-mediated biological events, such as smooth muscle relaxation, intraocular pressure, pain (in particular inflammatory, neuropathic and visceral pain), inflammation, neuroprotection, lymphocyte differentiation, bone metabolic processes, allergic activities, promotion of sleep, renal regulation, gastric or enteric mucus secretion and duodenal bicarbonate secretion. Prostaglandin E2 has been implicated in the stimulation of bone growth through the EP4 receptor subtype (Machwate et al., Prostaglandin receptor EP4 mediates the bone anabolic effects of PGE2. Molecular Pharmacology 60, 36).
A variety of EP4 agonists have been described and include, without limitation, compounds as set forth in, for example, WO 02/24647, WO 02/42268, EP 1132086, EP 855389, EP 1114816, WO 01/46140, WO 01/72268. Many EP4 agonists have however been associated with systemic side effects.
Bisphosphonates are drugs used to strengthen bone as they have been implicated in inhibiting bone resorption and bone targeting (L. Gil et al., Prostaglandin E2-bisphosphonate conjugates: potential agents for treatment of osteoporosis. Bioorganic & Medicinal Chemistry 7, 901).
Prostaglandin-bisphosphonate conjugate compounds are described in, for example, U.S. Pat. No. 5,409,911, U.S. Pat. No. 6,121,253 and WO 2011/147034.
Cathepsin-K (Cat-K) is an osteoclast protease (F. Lecaille et al., Selective inhibition of the collagenolytic activity of human cathepsin K by altering its S2 subsite specificity. Biochemistry 41, 8447).